Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders that cause dementia and hence are a major health concern. Both diseases affect the elderly and are increasing in prevalence as the aging population increases. These diseases are both associated with pathological changes in the brain including the deposition of abnormal proteins. Alzheimer's disease is associated with deposition of the proteins beta-amyloid and tau, whereas recently FTLD has been shown to be associated with the transactive response DNA binding protein 43 (TDP-43). We recently demonstrated that almost 50% of patients with AD also have deposition of the protein TDP-43 in their brain cells. This finding may be an important clue to understanding the underlying disease mechanisms causing FTLD and AD. However, it is currently unknown whether the role of TDP-43 in AD differs from its role in FTLD and whether TDP-43 deposition in AD has any clinical significance. The main objective of this R01 is to better understand the role, and hence significance, of TDP-43 in FTLD and AD. To accomplish this goal we will study a large cohort of autopsy confirmed cases of AD and FTLD that were ascertained through our NIH funded Alzheimer's Disease Research Center. We will assess and compare pathological characteristics of TDP-43 in FTLD and AD including its distribution, intracellular appearance, association with tau, and protein fragmentation. Associations between pathological characteristics and clinical and imaging characteristics will then be determined. Imaging-pathological associations will be investigated using state of the art automated imaging techniques, including voxel-based morphometry and atlas-based parcellation. The methods will be performed by a team of world renowned scientists including a dementia and movement disorder specialist, a neuropathologist, radiology researchers, and biostatisticians. The long term goal of our research is to aid in the development of treatments for AD and FTLD that will likely target underlying proteins.